.png){kind=icon}
.png){kind=icon}
Return
Plakophilin-2 truncating variants impair cardiac contractility by disrupting sarcomere stability and organization
.png){kind=icon}
OA
AI
DOI：10.1126/sciadv.abh3995.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Progressive loss of cardiac systolic function in arrhythmogenic cardiomyopathy (ACM) has recently gained attention as an important clinical consideration in managing the disease. However, the mechanisms leading to reduction in cardiac contractility are poorly defined. Here, we use CRISPR gene editing to generate human induced pluripotent stem cells (iPSCs) that harbor plakophilin-2 truncating variants (PKP2tv), the most prevalent ACM-linked mutations. The PKP2tv iPSC-derived cardiomyocytes are shown to have aberrant action potentials and reduced systolic function in cardiac microtissues, recapitulating both the electrical and mechanical pathologies reported in ACM. By combining cell micropatterning with traction force microscopy and live imaging, we found that PKP2tvs impair cardiac tissue contractility by destabilizing cell-cell junctions and in turn disrupting sarcomere stability and organization. These findings highlight the interplay between cell-cell adhesions and sarcomeres required for stabilizing cardiomyocyte structure and function and suggest fundamental pathogenic mechanisms that may be shared among different types of cardiomyopathies.
Keywords:
PLURIPOTENT STEM-CELLS
HEART-MUSCLE CELLS
ALPHA-T-CATENIN
ARRHYTHMOGENIC CARDIOMYOPATHY
ADHERING JUNCTIONS
AREA-COMPOSITA
PATIENT
CARDIOMYOCYTES
MECHANISMS
LEADS
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.
Journal
IF:
12.5
Papers:
2.0W
Citations:
18.1W